Alkynylpurine compounds and production methods thereof

Abstract

The present invention relates to alkynylpurine compounds represented by the following formula (I-1) and the formula (I-2): wherein each symbol is as defined in the present specification, salts thereof, and production methods thereof. According to the present invention, a method of producing an alkynylpurine compound and a salt thereof useful as an intermediate for medicament production safely, conveniently and economically from the corresponding purine compound and a salt thereof, as well as an alkynylpurine compound and a salt thereof useful as an intermediate for production of medicaments can be provided.

1 . A compound represented by the formula (I-1):  
     
       
         
         
             
             
         
       
       wherein  
       X 1  is an alkyl group, an alkoxy group, an aryl group, an optionally protected amino group, a halogen atom or a hydrogen atom,  
       one of Y 1  
 is a group represented by the formula: R—C≡C—
 wherein R is a hydrogen atom, a hydrocarbon group optionally having substituents, an aryl group optionally having substituents or a heterocyclic group optionally having substituents, and the other  
 
 Y 1  is a hydrogen atom, and  
 
       Z 1  is an alkyl group, a sugar group, an amino-protecting group or a hydrogen atom, which is attached to a nitrogen atom at the 7- or 9-position of the purine nucleus,  
       or a salt thereof.  
     
   
   
       2 . The compound of  claim 1 , wherein X 1  is a halogen atom, R is a hydrogen atom or Me 2 (OH)C—, and Z 1  is an amino-protecting group or a hydrogen atom.  
   
   
       3 . The compound of  claim 1 , wherein X 1  is a chlorine atom.  
   
   
       4 . The compound of any of  claim 1 , wherein Z 1  is tetrahydropyran-2-yl, benzyl or a hydrogen atom.  
   
   
       5 . A compound represented by the formula (1-2):  
     
       
         
         
             
             
         
       
       wherein  
       R is a hydrogen atom, a hydrocarbon group optionally having substituents, an aryl group optionally having substituents or a heterocyclic group optionally having substituents,  
       X 2  is an alkyl group, an alkoxy group, an aryl group, an optionally protected amino group, a halogen atom or a hydrogen atom, and  
       Z 2  is an alkyl group, a sugar group, an amino-protecting group or a hydrogen atom, which is attached to a nitrogen atom at the 7- or 9-position of the purine nucleus,  
       or a salt thereof.  
     
   
   
       6 . The compound of  claim 5 , wherein R is a hydrogen atom or Me 2 (OH)C—, X 2  is an optionally protected amino group, and Z 2  is an amino-protecting group or a hydrogen atom.  
   
   
       7 . The compound of  claim 5 , wherein Z 2  is tetrahydropyran-2-yl, benzyl or a hydrogen atom.  
   
   
       8 . A production method of a compound represented by the formula (I-I′):  
     
       
         
         
             
             
         
       
       wherein  
       X 1  is an alkyl group, an alkoxy group, an aryl group, an optionally protected amino group, a halogen atom or a hydrogen atom,  
       Z 1  is an alkyl group, a sugar group, an amino-protecting group or a hydrogen atom, which is attached to a nitrogen atom at the 7- or 9-position of the purine nucleus, and  
       one of Y 1′  is a group represented by the formula: Me 2 (OH)C—C≡C—, and the other Y 1′  is a hydrogen atom,  
       or a salt thereof, which comprises reacting a compound represented by the formula (II-1):  
       
         
           
           
               
               
           
         
       
       wherein  
       X 1  and Z 1  are as defined above, and  
       one of L 1  is a halogen atom, and the other L 1  is a hydrogen atom, provided that when X 1  is a halogen atom, L 1  is a halogen atom having higher leaving ability than the halogen atom represented by X 1 ,  
       or a salt thereof, with a compound represented by the formula (III): Me 2 (OH)C—C≡CH, in the presence of a metal catalyst and a base (1).  
     
   
   
       9 . A production method of a compound represented by the formula (I-1″):  
     
       
         
         
             
             
         
       
       wherein  
       X 1  is an alkyl group, an alkoxy group, an aryl group, an optionally protected amino group, a halogen atom or a hydrogen atom,  
       Z 1  is an alkyl group, a sugar group, an amino-protecting group or a hydrogen atom, which is attached to a nitrogen atom at the 7- or 9-position of the purine nucleus, and  
       one of Y 1″  is a group represented by the formula: HC≡C—, and the other Y 1″  is a hydrogen atom,  
       or a salt thereof, which comprises treating a compound represented by the formula (I- I′):  
       
         
           
           
               
               
           
         
       
       wherein  
       X 1  and Z 1  are as defined above, and  
       one of Y 1′  is a group represented by the formula: Me 2 (OH)C—C≡C—, and the other Y 1′  is a hydrogen atom,  
       or a salt thereof, with a base (2).  
     
   
   
       10 . A production method of a compound represented by the formula (I-1′″):  
     
       
         
         
             
             
         
       
       wherein  
       X 1  is an alkyl group, an alkoxy group, an aryl group, an optionally protected amino group, a halogen atom or a hydrogen atom,  
       Z 1  is an alkyl group, a sugar group, an amino-protecting group or a hydrogen atom, which is attached to a nitrogen atom at the 7- or 9-position of the purine nucleus, and  
       one of Y 1′″  is a group represented by the formula: A-C≡C—, wherein A is an aryl group optionally having substituents or a heterocyclic group optionally having substituents, and the other Y 1′″  is a hydrogen atom,  
       or a salt thereof, which comprises reacting a compound represented by the formula (I-1″):  
       
         
           
           
               
               
           
         
       
       wherein  
       X 1  and Z 1  are as defined above, and  
       one of Y 1″  is a group represented by the formula: HC≡C—, and the other Y 1″  is a hydrogen atom,  
       or a salt thereof, with a compound represented by the formula (IV): A-X wherein A is as defined above, and X is a halogen atom, in the presence of a metal catalyst and a base (1).  
     
   
   
       11 . A production method of a compound represented by the formula (I-1′″):  
     
       
         
         
             
             
         
       
       wherein  
       X 1  is an alkyl group, an alkoxy group, an aryl group, an optionally protected amino group, a halogen atom or a hydrogen atom,  
       one of Y 1′″  is a group represented by the formula: A-C≡C—, wherein A is an aryl group optionally having substituents or a heterocyclic group optionally having substituents, and the other Y 1′″  is a hydrogen atom, and  
       Z 1  is an alkyl group, a sugar group, an amino-protecting group or a hydrogen atom, which is attached to a nitrogen atom at the 7- or 9-position of the purine nucleus,  
       or a salt thereof, which comprises the following steps (a)-(c):  
       (a) a step of obtaining a compound represented by the formula (I-1′):  
       
         
           
           
               
               
           
         
       
       wherein  
       X 1  is an alkyl group, an alkoxy group, an aryl group, an optionally protected amino group, a halogen atom or a hydrogen atom,  
       Z 1  is an alkyl group, a sugar group, an amino-protecting group or a hydrogen atom, which is attached to a nitrogen atom at the 7- or 9-position of the purine nucleus, and  
       one of Y 1′  is a group represented by the formula: Me 2 (OH)C—C≡C—, and the other Y 1′  is a hydrogen atom,  
       or a salt thereof, which comprises reacting a compound represented by the formula (II-1):  
       
         
           
           
               
               
           
         
       
       wherein  
       X 1  and Z 1  are as defined above, and  
       one of L 1  is a halogen atom, and the other L 1  is a hydrogen atom, provided that when X 1  is a halogen atom, L 1  is a halogen atom having higher leaving ability than the halogen atom represented by X 1 ,  
       or a salt thereof, with a compound represented by the formula (III): Me 2 (OH)C—C≡CH, in the presence of a metal catalyst and a base (1),  
       (b) a step of obtaining a compound represented by the formula (I-1″):  
       
         
           
           
               
               
           
         
       
       wherein  
       X 1  and Z 1  are as defined above, and  
       one of Y 1″  is a group represented by the formula: HC≡C—, and the other Y 1″  is a hydrogen atom, or a salt thereof, which comprises treating a compound of the formula (I-1′) obtained in the step (a) or a salt thereof with a base (2), and  
       (c) a step of reacting a compound of the formula (I-1″) obtained in the step (b) or a salt thereof, with a compound represented by the formula (IV): A-X wherein A is an aryl group optionally having substituents or a heterocyclic group optionally having substituents, and X is a halogen atom, in the presence of a metal catalyst and a base (1).  
     
   
   
       12 . A production method of a compound represented by the formula (I-2′):  
     
       
         
         
             
             
         
       
       wherein  
       X 2  is an alkyl group, an alkoxy group, an aryl group, an optionally protected amino group, a halogen atom or a hydrogen atom, and  
       Z 2  is an alkyl group, a sugar group, an amino-protecting group or a hydrogen atom, which is attached to a nitrogen atom at the 7- or 9-position of the purine nucleus,  
       or a salt thereof, which comprises reacting a compound represented by the formula (11-2):  
       
         
           
           
               
               
           
         
       
       wherein  
       X 2  and Z 2  are as defined above, and  
       L 2  is a halogen atom, provided that when X 2  is a halogen atom, L 2  is a halogen atom having higher leaving ability than the halogen atom represented by X 2 , or the same halogen atom as X 2 , or a salt thereof, with a compound represented by the formula (III): Me 2 (OH)C—C≡CH, in the presence of a metal catalyst and a base (1).  
     
   
   
       13 . A production method of a compound represented by the formula (1-2″):  
     
       
         
         
             
             
         
       
       wherein  
       X 2  is an alkyl group, an alkoxy group, an aryl group, an optionally protected amino group, a halogen atom or a hydrogen atom, and  
       Z 2  is an alkyl group, a sugar group, an amino-protecting group or a hydrogen atom, which is attached to a nitrogen atom at the 7- or 9-position of the purine nucleus,  
       or a salt thereof, which comprises treating a compound represented by the formula (1-2′):  
       
         
           
           
               
               
           
         
       
       wherein  
       X 2  and Z 2  are as defined above,  
       or a salt thereof, with a base (2).  
     
   
   
       14 . A production method of a compound represented by the formula (1-2″′):  
     
       
         
         
             
             
         
       
       wherein  
       A is an aryl group optionally having substituents or a heterocyclic group optionally having substituents,  
       X 2  is an alkyl group, an alkoxy group, an aryl group, an optionally protected amino group, a halogen atom or a hydrogen atom, and  
       Z 2  is an alkyl sugar group, an amino-protecting group or a hydrogen atom, which is attached to a nitrogen atom at the 7- or 9-position of the purine nucleus,  
       or a salt thereof, which comprises reacting a compound represented by the formula (I-2″):  
       
         
           
           
               
               
           
         
       
       wherein  
       X 2  and Z 2  are as defined above,  
       or a salt thereof, with a compound represented by the formula (IV): A-X, wherein A is as defined above, and X is a halogen atom, in the presence of a metal catalyst and a base (1).  
     
   
   
       15 . A production method of a compound represented by the formula (I-2′″):  
     
       
         
         
             
             
         
       
       wherein  
       A is an aryl group optionally having substituents or a heterocyclic group optionally having substituents,  
       X 2  is an alkyl group, an alkoxy group, an aryl group, an optionally protected amino group, a halogen atom or a hydrogen atom, and  
       Z 2  is an alkyl group, a sugar group, an amino-protecting group or a hydrogen atom, which is attached to a nitrogen atom at the 7- or 9-position of the purine nucleus,  
       or a salt thereof, which comprises the following steps (a)-(c):  
       (a) a step of obtaining a compound represented by the formula (I-2′):  
       
         
           
           
               
               
           
         
       
       wherein  
       X 2  is an alkyl group, an alkoxy group, an aryl group, an optionally protected amino group, a halogen atom or a hydrogen atom, and  
       Z 2  is an alkyl group, a sugar group, an amino-protecting group or a hydrogen atom, which is attached to a nitrogen atom at the 7- or 9-position of the purine nucleus,  
       or a salt thereof, which comprises reacting a compound represented by the formula (II-2):  
       
         
           
           
               
               
           
         
       
       wherein  
       X 2  and Z 2  are as defined above, and  
       L 2  is a halogen atom, provided that when X 2  is a halogen atom, L 2  is a halogen atom having higher leaving ability than the halogen atom represented by X 2 , or the same halogen atom as X 2 , or a salt thereof, with a compound represented by the formula (III): Me 2 (OH)C—C≡CH, in the presence of a metal catalyst and a base (1),  
       (b) a step of obtaining a compound represented by the formula (I-2″):  
       
         
           
           
               
               
           
         
       
       wherein  
       X 2  and Z 2  are as defined above,  
       or a salt thereof, which comprises treating a compound of the formula (I-2′) obtained in the step (a) or a salt thereof, with a base (2), and  
       (c) a step of reacting a compound of the formula (I-2″) obtained in the step (b) or a salt thereof, with a compound represented by the formula (IV): A-X, wherein A is an aryl group optionally having substituents or a heterocyclic group optionally having substituents, and X is a halogen atom, in the presence of a metal catalyst and a base (1).  
     
   
   
       16 . The production method of  claim 8 , wherein the metal catalyst is a palladium compound.  
   
   
       17 . The production method of  claim 8 , wherein the metal catalyst is a combination of a palladium compound and a copper compound.  
   
   
       18 . The production method of  claim 17 , wherein the palladium compound is bis(triphenylphosphine)palladium dichloride or tetrakis(triphenylphosphine)palladium.  
   
   
       19 . The production method of  claim 17 , wherein the copper compound is at least one selected from cuprous iodide, cuprous bromide and cuprous chloride.  
   
   
       20 . The production method of  claim 8 , wherein the base (1) is trialkylamine.  
   
   
       21 . (canceled)  
   
   
       22 . The production method of  claim 20 , wherein the trialkylamine is triethylamine or ethyldiisopropylamine.  
   
   
       23 . The production method of  claim 9 , wherein the base (2) is alkali metal hydroxide or alkali metal carbonate.  
   
   
       24 . The production method of  claim 10 , wherein the metal catalyst is a palladium compound.  
   
   
       25 . The production method of  claim 10 , wherein the metal catalyst is a combination of a palladium compound and a copper compound.  
   
   
       26 . The production method of  claim 25 , wherein the palladium compound is bis (triphenylphosphine) palladium dichloride or tetrakis (triphenylphosphine) palladium.  
   
   
       27 . The production method of  claim 25 , wherein the copper compound is at least one selected from cuprous iodide, cuprous bromide and cuprous chloride.  
   
   
       28 . The production method of  claim 10 , wherein the base (1) is trialkylamine.  
   
   
       29 . The production method of  claim 28 , wherein the trialkylamine is triethylamine or ethyldiisopropylamine.